Mud Therapy and Rehabilitation - Scientific Relevance in the Last Six Years (2015 – 2020) a M M E E

Balneo and PRM Research Journal • Volume 12, Number 1 • March 2021 REVIEWS

W W E E I I V V E E R R

c c i i t t a Mud therapy and rehabilitation - scientific relevance in the last six years (2015 – 2020) a m m e e

t Systematic literature review and meta-analysis based on the PRISMA paradigm t s s

y y S S

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s s w w e 1,2,3 1,3 1,5,6 e i MUNTEANU Constantin , ROTARIU Mariana , DOGARU Gabriela , i v v e 7,8 9 2,3 e R IONESCU Elena Valentina , CIOBANU Vlad , ONOSE Gelu R

Editor: Mihail HOTETEU, Romanian Association of Balneology, [email protected]

Authors: 1. Romanian Association of Balneology, Bucharest, Romania Prof. dr. Gelu Onose, Ph.D. 2. Teaching Emergency Hospital ”Bagdasar-Arseni”, Bucharest, Romania Senior Physician in Physical and 3. Faculty of Medical Bioengineering, University of Medicine and Pharmacy “Grigore T. Popa”, ,D܈L, Rehabilitation Medicine (PRM) and Romania Gerontology & Geriatrics (GG) Head of the P(neural-muscular)RM 4. Faculty of Medicine, Department of Physical and Rehabilitation Medicine, University of Medicine and Discipline/ Clinic Division - the National Pharmacy ”Carol Davila”, Bucharest, Romania Reference Centre for NeuroRehabilitation - and of its RDI 5. Faculty of Medicine, University of Medicine and Pharmacy “,XOLX+D܊LHJDQX”, Cluj-Napoca, Romania Nucleus, and RDI (ex) Director, at the 6. Clinical Rehabilitation Hospital Cluj-Napoca, Romania Teaching Emergency Hospital 7. Balneal and Rehabilitation Sanatorium Techirghiol&RQVWDQ܊D5RPDQLD "Bagdasar-Arseni" 8. Faculty of Medicine, ³2YLGLXV´8QLYHUVLW\RI&RQVWDQ܊DRomania Lecturer dr. Constantin Munteanu, Ph.D. Priority research areas: 9. Computer Science Department, University Politehnica of Bucharest, Romania Bioclimatology, Hydrothermotherapy, and Abstract Physiology, President of the Romanian Association of Balneology, Background. Balneotherapy is a stimulation - adaptation treatment method applied in the forms of Vice President of the Romanian bathing, drinking, and inhalation cures performed with natural therapeutic factors, a method which is Society of Physical Medicine, Rehabilitation and Balneoclimatology, acting in three main ways: thermally, mechanically, and chemically. Mud or peloids are natural therapeutic factors formed by natural processes under the influence of biological and geological Assoc. prof. dr. Mariana Rotariu, Ph.D. - Kinesiology, Psychomotricity, phenomena, which in a finely dissolved state and mixed with water (mud) are used in medical practice psychomotor education and in the form of baths or local procedures. reeducation, Kinesitherapy. Objective. This systematic review aims to rigorously select related articles and identify within their Kinesiprophilaxy, Massage. Complementary techniques, content, the main possible uses of therapeutic mud and physiological mechanisms, to see the main Occupational therapy, Rehabilitation, region of scientific interest for pelotherapy, and to discuss the value of mud therapy in rehabilitation and techniques of functional medicine. reeducation

Methods. The working method is based on the Preferred Reporting Items for Systematic Reviews and Assist. prof. dr. Gabriela Dogaru, PhD Meta-Analyses (PRISMA) guidelines. We searched for open-access articles published in English, Priority research areas: between January 2015 and December 2020, from the following databases: Cochrane, Elsevier, balneoclimatology, including the study of carbonated mineral waters and NCBI/PubMed, NCBI/PMC, PEDro, and ISI Web of Knowledge/Science (the latter was also used to mofettes, molecular and cellular identify ISI indexed articles). The contextually searched syntax used was medicine, e-health systems, ”Pelotherapy/Peloidotherapy/Mud-therapy/ /Fango-therapy AND Rehabilitation”. The selected articles neurological and cardiovascular rehabilitation, development of spa, were analyzed in detail regarding pathologies addressed by mud therapy and country scientific and rehabilitation tourism. relevance for this therapeutic method. The meta-analysis proceeded was designated to estimate the Assoc. prof. dr. Elena Valentina prevalence of various pathologies in the use of mud therapy. IONESCU, PhD Results. Our search identified, first, 394 articles. Based on the successive filtering stages and, Priority research areas: Bioclimatology, respectively, on the classification criteria of the Physiotherapy Evidence Database (PEDro), we finally Hydrothermotherapy, and Medical rehabilitation, Medical Director of identified/retained and analyzed 68 articles. Although, in principle, a rigorous method – and we have Balneal and Rehabilitation Sanatorium followed the PRISMA type paradigm – there still might be some missing works of our related article Techirghiol selection. On the other hand, to augment/ consolidate our documentation base, we have used also 40 papers freely found in the literature, and even – aiming, too, at an as exhaustive knowledge Assist. prof. dr. Vlad Ciobanu, PhD An experienced IT professional underpinning as possible – derogatively, we have also considered some articles which, probably being specialized in solution architecture and very new, couldn't yet have reached the PEDro threshold score we have settled. design of software and hardware Conclusions. This paper overviews the current state-of-the-art knowledge in the approach of systems with nine years’ software development experience within a peloidotherapy in rehabilitation, with a focal point on the therapeutic properties of peloids. commercial software development

environment. Keywords: mud-therapy, pelotherapy, peloidotherapy, fango therapy, rehabilitation, balneotherapy, natural therapeutic factors, Reviewers: ^ŝůŝƕƚĞĂŶƵ^ŠŶǌŝĂŶĂĉůŝŶĂ͕WŚ ^ƚĉŶĞƐĐƵ/Žana, PhD Corresponding author: Constantin MUNTEANU, E-mail: [email protected]

DOI: http://dx.doi.org/10.12680/balneo.2021.411 Vol.12, No.1, March 2021 p: 1–15 http://bioclima.ro/Journal.htm 1

1. INTRODUCTION Collectively, the spa economy is estimated at $94 billion, skin health. The beneficial effects of the mud and salt with a consistent growth perspective in the coming from the Dead Sea (11) led her to ask Marc Antonius to decades. The general context of spa environments can conquer this region to benefit from this remedy. support a holistic approach to health promotion (1). Therefore, the use of Dead Sea (14) mud for therapeutic Basic components of health resort interventions - spa purposes dates back thousands of years, from the time of therapies (2) - are balneotherapy (3) and climatotherapy. the Roman Empire. In many countries, treatments involving natural mineral We have more accurate data on the use of mud from the waters, gases, or peloids (4) are referred to as 14th century, in a paper that talks about the use of balneotherapy. Routes of application include bathing, therapeutic mud from Albano and Battaglia, and inhalations, drinking (Crenotherapy), etc. (5), often Fallopius describes in 1564 the technique of using mud. encompassing rehabilitation objectives/procedures (6)(7). Later, mud therapy (pelotherapy/peloidotherapy) is used According to the definition given by the "International in France (seventeenth century) and Germany (eighteenth Society of Medical Hydrology", muds (peloids) and clays century). In Russia, the cradle of pelotherapy is the (8) are "substances formed in natural conditions under the Crimean peninsula. influence of geological processes and which, mixed with Last but not least, Romania is a country famous for its water (9), are used in medical practice in the form of balneary resorts. For renowned mud deposits, baths or local procedures (10). Techirghiol, Sovata, Ocna Sibiului, Mangalia, Amara are Muds are earths or rocks of a pasty consistency, used as the main resorts promoted for mud therapy. therapeutic remedies or cosmetics (11) from remote The complex interdisciplinary characterization of the times. Some beneficial effects of mud are known natural therapeutic factors necessarily includes empirically from antiquity, others have been described interpretation of physicochemical analyzes and and studied quite recently, some have remained today in microbiological (15)(16) examinations. the stage of summary explanation. Mud treatment is also Classification of muds (17) called pelotherapy (9), peloidotherapy, or sometimes – a Clay (18) has been used by humans since before recorded largely – fango therapy. Pelotherapy should be used only history to accomplish basic but fundamental healthcare as directed and under medical supervision (8). purposes. The clay plates of Nippur, Mesopotamia, which From ancient times people used mud, when they had it at date back to about 2500 BC, contain a reference to the their disposal, for healing or beautification (12). use of clays for therapeutic purposes, including the Archaeological artifacts support such a hypothesis and treatment of wounds and the inhibition of hemorrhages. there are no problems in understanding these data since Also, the famous Papyrus Ebers dated about 1600 BC the instinct to seek healing remedies also exists for the describes the treatment of some diseases using clay-based animal world, argued by new data also (13). Even if medicines. Since then, from Ancient Greece, Roman images in which the pig rolls in the mud for comfort times, medieval times, renaissance times to contemporary seem legendary, or from a fairy-tale, we can only admit times, there exist reports on the therapeutic, nutritional that such behavior is explainable in the equation of an and cosmetic uses of clay and clay-based products (8). adaptive benefit. The use of mud has its origins in There are several types of clay and within them, the so- antiquity. In ancient Egypt, the sick were anointed with called healing clay (19) and edible clay had been used the mud brought by the Nile during the floods. and are still being used, by man for therapeutic, The most common therapeutic muds are deposits in nutritional, and cosmetic purposes. Edible clay is a saline basins - black sulfurous muds, which form on the particular type of healing clay which use is limited to bottom of marine estuaries, bays, and continental salt internal application through ingestion, for instance, of lakes. The activity of quality evaluation for the resources cookies made of clay/ /potable water of natural therapeutic substances begins by taking dispersion/suspension. Conceptually healing clay besides samples at source and ends with their complex the oral use for internal health benefits of the digestive interdisciplinary characterization, being developed tract (20) can also be used in external or topical indications and contraindications for prophylaxis, therapy applications as clay and mineral water paste called mud and/or rehabilitation by conducting a complete or peloid for the treatment of muscle-skeletal and pharmacodynamic study. dermatological disorders (8)(21). In one of his works, Pliny (23-79 AD) recommends the Peloid is a maturated mud or muddy dispersion with use of mud, a recommendation made by Dioskorides (50 healing and/or cosmetic properties, composed of a AD) in his works and later also by Galen (131-2020 AD). complex mixture of fine-grained natural materials of In antiquity, Cleopatra's behavior is historically geologic and/or biologic origins, mineral water or emphasized, considered a beauty of her time, in terms of seawater, and common organic compounds from bodily maintenance, an aspect directly correlated with biological metabolic activity.

NATURAL peloids are formed by depositing more or resulting in the content of organic substances in dry less decayed, rotten, overripe, organic, and inorganic mud below 10%; substances in bayous, sea lagoons, saltwater and  incomplete transformation of the vegetal material in freshwater lakes, rivers, marshes, mineral water spring conditions of advanced humidity - swamps, resulting mires, and volcanic areas (22). in the content of organic substances in dry mud of ARTIFICIAL peloids are natural clays that are refined over 10%; and significantly changed before their use (23).  salty clays and marls, sedimented in arid land According to their origin: conditions - lagoons from the biological past; ORGANIC PELOIDS comprise those peloids consisting  calcareous tuffs, formed by chemical precipitation - of over 10% of organic substances: around natural carbon dioxide emergencies.  peat (peat soil, elevated and leveled peat) (24)(25) Fangotherapy - is a particular type of pelotherapy that  organic mud (bitumen mud, sapropel and Gyttja)(8) involves the use of fango name of Italian origin attributed INORGANIC PELOIDS (8) comprise: to muddy natural peloids deposited from thermal springs  mineral peloids (clay, loam, tufa) as happens in the case of the Euganean volcanic region,  volcanic peloids (8) in Italy, where important Thermal Resorts exist (8). Depending on the formation conditions and the chemical Chemical composition of peloids (26)(27) composition, the therapeutic muds are classified into: From a physicochemical point of view, the mud is a a) Sapropelic muds - are represented by black deposits, heterogeneous system (28) consisting of a liquid phase rich in colloidal iron hydrosulfide, have a plastic and containing water and water-soluble mineral salts, a solid greasy appearance, are found on the bottom of salt waters phase containing mineral and organic substances, and a originating from the action of microorganisms on the gaseous phase containing hydrogen sulfide (29). flora and fauna of the aquatic basin to which minerals or The ionic balance of mud is also reflected in its pH. In inorganic substances that come from the soil of the lake general, the mud is alkaline pH = 9 – 10 (30). basin are associated. Their content in organic substances The therapeutic effect of mud is given by the is greater than 10% to the weight of the dry matter - combination of its physical and chemical properties (31). continental lake, lagoon; LIQUID PHASE The flora consists of microphyte and macrophyte algae in It is the solution of imbibition - the aqueous solution of which Cladophora vagabunda, Cladophora cristalina, organic and inorganic substances predominates, algae that grow only in saltwater. Depending on its proportion muds are divided into: The aquatic fauna is represented by the species Artemia  poorly hydrated with moisture content <37% salina 10 - 12 mm, red arthropods. The carcasses of  medium hydrated by weight humidity = 37-40% Artemia salina, by bacterial decomposition, together with  strongly hydrated with a moisture content> 40% the alga Cladophora cristalina, form the sapropelic mud. The liquid phase results from the water of the lakes in the Sapropelic muds are black deposits underwater sediments basin of which the mud is produced rainfall, and impact rich in colloidal iron hydrosulfide, plastic and greasy. of mineral waters. Depending on the predominant ions b) Mineral and vegeto-mineral muds appear by (32), it may have a different character: sulfated, sedimentation of the salts of some springs with sulfidic, carbonated, or mixed, and with the following content: ferruginous, carbogazeos character. Mineral muds - arise • Water, anions, cations (33), by the sedimentation of salts of carbonaceous, calcium, • Oligoelements (ug/kg) (28) ferruginous or sulfurous springs; 1. with pharmacological effect (Fe, Co, J, Br, and B) c) Peat (humus vegetabilis lutosa) - organic, brown mud. 2. involved in the enzymatic processes (J, Fe, Cu, Mo, Peat muds result from the microbiological decomposition Zn, Co, Mn, Ni, Ba, Sr, Cd) of the remains vegetables accumulated on the bottom of 3. non-essential/toxic elements (As, Pb, Hg, V, and F) some swamps. Their content in organic substances is also 4. not yet elucidated biological role (Ti, Zr, Ir, Cs). greater than 10% of the weight of the dry matter (24). • Biologically active substances - protein hydrolysates, Peat is formed in the following ways: amino acids, enzymes (34).  natural formation through physicochemical and GASEOUS PHASE - results from the physicochemical microbiological processes at the contact of the and biochemical processes involved in the mud formation mineral water with the clay bed, around the natural (peloidogenesis): H2S, CO2, NH4, CH4, O2, Rn (8) emergents, resulting in the content of organic Hydrogen sulfide (H2S) is also an endogenous gas with substances in dry mud below 10%; important physiological functions (35). Endogenous  directed formation through microbiological and hydrogen sulfide has been reported to function as a physicochemical processes at the contact of the neuromodulator in the brain and within the vasculature; mineral water with the clay bed - artificial basins - the main functions of H2S are vasodilation and promoting new vessel growth (36).

SOLID PHASE Methods of mud applications • Crystal framework (peloid skeleton) – determines the  Mud baths, full, half body, or arm-leg - in tubs with mechanical structure heated lake water in which 10 - 12 kg of mud are • Oxides (SiO2, Al2O3, Fe2O3, CaO, MgO, Na2O, added, progressively increasing its concentration up to K2O, TiO2, MnO, P2O5), Na2O/CaO < 1 10 - 25%. The mixture can be heated to 42 ° C (43). In • Colloid complex - plastic hydrophilic basis which the case of patients with cardiovascular diseases, the absorbs moisture and defines thermal properties temperature should not exceed 37ºC, and for those • Inorganic component Fe(HS)3, Fe(OH)3, Al(OH)3, with inflammatory rheumatic diseases below 36ºC. H2SiO3 The duration of the bath is 20 ´- 40´. The bath must be • Organic component – humic substances: humin, followed by a shower at 37º - 38ºC and a rest of at humic and fulvic acids (34) least one hour. A cure consists of 12-15 daily baths. Humic substances are generally considered to have  Mud Packages applications: peloids are applied to occurred during the humidification process of the organic specific areas of the body (44) material. Their color varies from yellow to black,  Mud anointing - is the oldest method that involves molecular mass from 2000 to over 300,000 Da, have a C applying cold mud on the patient's skin, after it has content between 45 and 62%, O between 30 and 48%, been heated 10̕-15̕, in a thin layer, on limited areas or and free acidity between 500 and 1400 mEq% (37). the whole body. The patient should then be exposed to The heterogeneity of the molecular weight of many the sun, in an upright position, until the mud dries, individual compounds with different chemical approximately 30 - 60´, followed by a bath of 10´ - compositions containing biogenic elements (C, N, O, P, 15´ in sea or lake water accompanied by movement S) in carboxyl, phenol, alcohol, peptide, amide, and other and a short shower with cold water and bed rest for at functional groups causes humic substances to be least an hour. It is a method of stressing the polydisperse, heterogeneous, biophilic and mechanisms of thermoregulation, neuroendocrine multifunctional (37). stimulation, and adaptation processes by alternating The mud can be fractionated using the variation of pH hot-cold contrasting factors. and polarity of solvents and humic extracts can be  Mud wraps - consist of applying mud in a layer of 1 - characterized spectrophotometrically based on absorption 2 cm heated to 38º - 46ºC on a limited region or the in the wavelength range 340-700 nm, humic acids, and entire body surface for 20´ - 40´. fulvic acids being differentiated based on solubility and  Poultices - applications with mud at different molecular weight. Briefly, the mud is treated with a KOH temperatures on limited regions of the body (24). solution, obtaining the alkaline extract of soluble humates  Gynecological applications - in the form of vaginal and fulvates and the precipitation of insoluble humin(37). swabs with mud at 39º - 40ºC for 2 hours or vaginal Physical properties of mud (38)(27) irrigation with mud dissolved in lake water and heated  Specific weight - depends on the components to 37ºC (43). mineral substances > organic substances, is  Mud massage - stretching and mud massage maximum for strongly mineralized muds, minimum Application method: for peat muds 1. After application, the body gets freed of mud with the  Hydropexy: water absorption and retention capacity, assistance of a warm shower (taken under the water practical value - peloids with low hydropexy (mineral in temperatures of 37-38 ºC). mud) are used only for packaging, those with medium 2. The patient gets dried of immediately and rests for hydropexy (sapropelic mud) and high (peat mud) can half an hour to an hour. also be used for baths. 3. Afterward, the patient either takes a light walk or  Plasticity: the property of stretching and molding on receives a massage, or is taken into an adequate the surface of the body - is given by the solids in their exercise program, if necessary. content; low plasticity (mineral mud), medium (peat), Main peloid actions: and high (sapropelic) (25)  cardiovascular system - stimulation of cardiovascular  Thermopexy: heat absorption and storage - peloids reactions with accentuation of hemodynamics by have a high ability to retain heat (39)(40). central and peripheral mechanisms. Immediate  Consistency – it depends on the viscosity conditions mobilization of blood deposits and their involvement the frictional force that is exerted on the skin when in the general circulation takes place; cutaneous applied (40) vasodilation → increases cardiac output (45)  Specific heat - represents no. of calories to raise the  nervous system - sedative or exciting effects on the heat of one gram of mud by one degree (40)(41)(42) CNS and SNV by sedating pain receptors (46).  Granulometry - the degree of mud dispersion and the  The mud bath determines the increase of the size of the solid particles (41) antimicrobial defense capacity by increasing the

phagocytic power of the leukocytes - highlighted by  regulating the balance of homeostasis through the changes of the opsono-cytophagic index immune, endocrine, and neurovegetative  digestive: determines the balance of gastric secretion, mechanisms (47)(52); increases biliary secretion  better oxygenation of tissues (an increase of SO2%  renal: decreases renal secretion and diuresis (when in peripheral blood, O2 binding capacity, and oxy- perspiration is stimulated) hemoglobin).  tissue: tissue hydrophilicity changes → increases The thermal effect of peloidotherapy determines: resorption capacity (chronic inflammation, bursitis)  pain relief (53);  immune system - regulation of immunoglobulin  decreased muscle contractions (54); values (47), an increase of non-specific immunity  anti-inflammatory effects - the higher the application (9)(48). temperature, the higher the tonic immuno-stimulatory and  The endocrine system. The enzymatic and metabolic cardiovascular effects, the application is possible due to changes that appeared in the endocrine glands after the special mud property of thermopexy. peloidotherapy differ according to the specific All of these develop local and general remote effects, secretion of the gland, according to the functional such as analgesic effect, anti-inflammatory, muscle stage in which the gland is located, and are related to relaxant, detoxifying, neuroendocrine, to regulate the type of therapeutic application. Under the action immunity (55) and because the (including) mud based of mud, there is a harmonic stimulation in all glands thermotherapy acts, as well, by enhancing the in the sense of increasing the enzymatic and synthetic elasticity of the conjunctive-collagen major activity while maintaining the specificity of each. musculo-entheso-articular constituents – Correlated with the activity of endocrine functional respectively through reducing their stiffness, which harmonization is the stimulation of the activity of the is associated to many conditions affecting such hypothalamic-pituitary-adrenal axis translated by optimizing the plasma levels of β-endorphins. Glands structures and/or to (just) aging – this, together with with internal secretion - ovarian, pituitary function are the above mentioned muscle decontracturant and stimulated. analgesic effects, results also in an important link to  The endocrine mechanism is also involved in inducing facilitating rehabilitation: with more supple, relaxed the anti-inflammatory (49) effects of pelotherapy by and pain freer segments of the body, is a biological modulating the activity of the hypothalamic-pituitary- state prone to better outcomes of kinesiotherapy/ adrenal axis and by the general balancing of the physical exercise, with consequent augmented endocrine balance, persistent effects, and post-cure. functional mobility recover, and thus, an overall  Reactivity to chemical mediators - acetylcholine and improvement of the quality of life, too. adrenaline - as well as to ions correlated with Pharmacodynamic properties vegetative activity - Ca, Mg, K - is increased after the Being a biological material used in human therapy, the external cure with mud, and the vegetative tone tends analysis is performed according to the methods indicated regulation/normalization, which leads to remediation in the "Romanian Pharmacopoeia" with some additions of vegetative stigmas. taken from the working methods used for soil analysis. Therapeutic effects of mud (50) The obtained result is presented in the form of the Through its composition and thermopexy properties, the physicochemical analysis bulletin. mud determines: When applying peloids, a series of processes take place at  stimulation of peripheral mechanoreceptors - the level of the skin: triggers reflex mechanisms with favorable effects;  sensitive reception of mud qualities/properties and  subsequently follows skin vasodilatation their transmission to the upper stages of integration (neurohumoral phase, with input made directly and control; through the thermal factor) - benefits the absorption  exchange of energy and substance with the peloid of elements present in the mud; environment;  bacteriostatic and bactericidal effects (51)(34)  fulfillment of adaptive functions: circulatory  exchanges of energy and substances (peripheral circulation of thermoregulation), secretory (thermoregulation of peripheral circulation, (sweating), protective (keratinogenesis, excretion, stimulation of skin repair processes) (2); melanogenesis, hydrolipid film formation);  general thermoregulation stress resulting in related  integration of skin - mud application effects in the optimized adaptive physiology and or therapeutic- general physiology of the body: thermoregulation, rehabilitative responses (2); vitamin D synthesis, optimization of homeostatic  vitamin D synthesis; balances: immune, endocrine, and neurovegetative of the body (17). 5

Applying mud to the entire surface of the skin triggers Contraindications local tissue and general functional reactions, inhibiting or o febrile/infectious or acute/subacute conditions - other activating some enzyme systems and intermediate than those for which the treatment is performed; metabolites. The mud spa treatment produces favorable o cardiovascular diseases; effects that persist for a long time by changing the ability o respiratory diseases: exacerbation of COPD, asthma to respond adaptively to various stimuli. with recent seizures, bronchiectasis, recent respiratory This procedure is a demanding one as the application infections; time, density and temperature are higher, respectively the o dermatological diseases: bedsores, suppurative higher the salt concentration of the dilution saltwater. wounds, eczema in the developmental stage, psoriatic Even in healthy, robust patients, this procedure is erythroderma. especially demanding for the cardiovascular system. That Mud therapy is contraindicated if the patient suffers from is why it is contraindicated especially in hyper and asthma, diabetes, ulcers, any form of cancer, or hepatitis, hypertensive patients. kidney, or cardiovascular disease. Peloiodotherapy is indicated for the following 2. METHOD conditions: Search Strategy. To fundament the above-mentioned - degenerative rheumatism with different locations: spine data synthesis we have achieved a related systematic (spondylosis, simple discopathy, chronic lumbago (56), literature review and meta-analysis. Accordingly, we peripheral (coxarthrosis, gonarthrosis) (57) have searched for relevant open access works, in 6 - osteoartritis (58)(59)(60)(61)(62)(63)(64)(65)(66)(67), international databases: including Cochrane1, Elsevier2, - inflammatory rheumatism (54) NCBI/PubMed3, NCBI/PMC4, PEDro5 , and ISI Web of - ab-articular rheumatism (68) Knowledge/Science6, published from January 2015 until - fibromyalgia (69)(70) December 2020. The contextually quested key words - musculoskeletal disorders (MSDs) (71)(72) combinations/ syntaxes used in this respect were: - post-traumatic sequelae (73) ”Pelotherapy /Peloidotherapy /Mud-therapy /Fango- - carpal tunnel syndrome (74) therapy AND Rehabilitation”. - central and peripheral nervous system damage (75) The eligible articles were analyzed in detail regarding - psoriasis (76)(34) pathologies addressed by mud therapy/ rehabilitation – - chronic eczema, chronic wounds (77) following a (Preferred Reporting Items for Systematic - chronic urticaria Reviews and Meta-Analyses – PRISMA7 – type filter/ - obesity (78) selection methodology – see Fig. 1) with additional - pituitary dwarf country scientific relevance specified for this therapeutic - rickets or children's weakness method. The meta-analysis proceeded was designated to - gynecological chronic inflammation, secondary sterility, estimate the prevalence of various pathologies in the use post-tuberculosis sequelae of mud therapy/ rehabilitation. The ability of therapeutic mud to effectively restore Inclusion and Exclusion Criteria reproductive function has long been known and does not Any relevant article that reported clinical or cause doubt. In mud resort centers for the treatment of physical/chemical or biological information regarding infertility applications and mud baths, vaginal and rectal peloids/mud therapy/ rehabilitation was included in the tampons with mud heated to the desired temperature. analysis. All articles with any design (reviews, The effect of mud therapy will be more visible if it is randomized controlled trials, non-randomized controlled combined with physical therapy (79) and gynecological trials, case-control studies, cross-sectional studies), if massage, with medical microclyms, reflexology, and eligible according to the above-mentioned selection homeopathy. methodology, were included. Mud treatment is indicated for patients with chronic Articles were excluded if they didn’t reach – using a inflammatory processes of different origins, with chronic weighted, own, PEDro inspired scoring classification – at adnexitis and peri-adnexitis, with different adhesions, least a score of 4 – ”fair quality” or mare points. with parameterized residues, with chronic endocervicitis 3. RESULTS and colitis, with some forms of infertility, with Our search identified, first, 394 articles. Based on the miscarriage. successive filtering stages and, respectively, on the Mud treatment is useful in case of insufficiency of ovarian function and mild forms of uterine 1 https://www.cochrane.org/ underdevelopment. Patients with severe genital lesions at 2 https://www.elsevier.com/ Trichomonas may go for a spa treatment. Amenorrhea 3 https://pubmed.ncbi.nlm.nih.gov/ 4 https://www.ncbi.nlm.nih.gov/pmc/ and dysmenorrhea - menstrual disorders - are also 5 https://pedro.org.au/ indications for mud therapy. 6 http://apps.webofknowledge.com/WOS_GeneralSearch 7 http://www.prisma-statement.org/ 6

classification criteria of the Physiotherapy Evidence osteoarthritis (OA) reveal the implications of Database (PEDro), we finally identified/retained and adipocytokines. In the last years, balneological research analyzed 68 articles (see Fig. 1). was directed towards the study of specific inflammatory Although, in principle, a rigorous method – and we have cytokines' involvement in musculoskeletal disorders. followed the PRISMA type paradigm – there still might Correlations between peloid therapy and inflammatory be some missing works of our related article selection. pathways, at a molecular level, are established and new On the other hand, to augment/ consolidate our insights into the world of chondrocytes and osteoblasts documentation base, we have used also 40 papers freely are brought to light (85). found in the literature, and even – aiming, too, at an as Peat obtained from Taean-gun, Chungcheongnam-do, exhaustive knowledge underpinning as possible – Korea, can be considered as a therapeutic option for pain derogatively, we have also considered some articles relief of knee OA patients. Although short-term peat which, probably being very new, couldn't yet have intervention did not have significant effects on serum reached the PEDro threshold score we have settled. cartilage oligomeric matrix protein, long-term follow-up Meta-analysis (80) assessment using several parameters, including pain and Afferent with the final step, we have done also a related OA biomarkers (86), is needed. The reduction in knee Meta-analysis, 26 studies were included in this step, joint varus/valgus range of motion and the increase in which count 15123 human subjects in total. The smallest gait velocity after peat intervention are meaningful results sample size was 32 and the largest was 6281. The meta- as effects of peat intervention on gait parameters (87). analysis (80) investigated the beneficial effects of mud Experts agree that the Spa therapies are effective in therapy on specific indicated diseases. controlling the symptoms and objective signs of disease Our obtained forest plot, also known as a blobbogram, in patients with musculoskeletal disorders, as well as in is a graphical display of estimated results from several ensuring a decrease in the recruitment of NSAIDs and scientific studies addressing the same question, along analgesics (88). with the overall results. Sometimes trials are just looking The hormetic effects of balneotherapy are related to at different concepts. Statistical heterogeneity is apparent different factors. The main factor that is common to all only after the analysis of the results. Heterogeneity may types of mineral-medicinal waters and muds is heat. be judged graphically (by looking at the forest plot) and The anti-aging properties of mud therapy (69) are an be measured statistically. In a forest plot from the exciting concept for prevention and slowing the aging systematic review, the error bars for each trial include the process throughout the entire body and other summary result, which suggests that statistical dermatological diseases. Therapeutic spas and baths offer heterogeneity is not a problem and that the message is a an atmosphere of health and physical fitness by their consistent one (fig 3). To determine whether significant chemical, thermal, mechanical, and endocrine actions. heterogeneity exists, a P-value high for the χ2 test of They also provide relaxation and stress relief. Mud heterogeneity is good news because it suggests that the therapy is effective individually or as a complement to heterogeneity is insignificant and that one can go ahead other medical therapies. Recently, the concept of thermal and summarise the results (81). mud therapy has been changing. During the aging 4. Relevant topical data regarding mud therapy process, endocrine changes result in a decline in in, Physical and Rehabilitation Medicine (PRM) and endocrine function involving the responsiveness of Balneology tissues as well as reduced hormone secretion from In vivo experimental models (82) based on murine peripheral glands. This is coupled with modifications in osteoarthritis or rheumatoid arthritis, to establish the the central mechanisms controlling the temporal actions of Hévíz mineral water and mud, Hungary (83) or organization of hormone release, with a dampening of Jeju Magma-Seawater, Korea (82) – by a modern circadian hormonal and non-hormonal rhythms. methodological approach using functional tests and Compared to younger individuals, healthy older morphological analysis – provided favorable Evidence- individuals have alterations in body composition and a Based data of Complementary and Alternative Medicine decline in functional status: decreased muscle mass, effects of these natural therapeutic-rehabilitative factors, increased fat mass, and decreased strength. Even with that can be observed clinically in OA patients, too. healthy aging, there are changes in endocrine systems, Articular diseases are the most frequent causes of chronic including estrogen (menopause), testosterone (andropause), pain and related disability. For instance, rheumatoid growth hormone/insulin-like growth factor-I axis arthritis (RA) is an autoimmune disease characterized by (somatopause), hypothalamic-pituitary-thyroid axis, synovial inflammation and progressive structural joint hypothalamic-pituitary-cortisol axis, and dehydro- damage. Osteoarthritis is a degenerative process of the epiandrosterone and its sulfate (adrenopause) (89). articular cartilage associated with hypertrophic changes H2S – which is also a biochemical component within the in the bone (84). The new insights in the pathogenesis of mud, as well as radon (90) – induces a wide range of

physiological responses such as blood pressure Thermal muds have been used in many spas for the modulation, neuromodulator in the brain and within the treatment of different diseases (medical uses) as well as vasculature, protective against ischemic reperfusion to clean and beautify the skin, in different forms/wellness injury, and anti-inflammatory reactions (36). H2S is an such as mud baths, masks, and cataplasms (94). DPSIR endogenous gasotransmitter, and, as such, it can be (Drivers-Pressures-State change-Impacts-Responses) (95) absorbed by numerous routes; it can penetrate the skin framework can be used also to analyze touristic activities, and mucosae and can therefore act at the cell level both in including mud uses, to identify a set of key indicators the skin (29) and in internal organs. Organic components with weightings for health tourism destinations by using of muds were demonstrated to have biological effects an advanced analytic hierarchy process (AHP) method, contributing to the healing mechanisms, but their medical derived from the official, academic, and professional significance is not still fully understood (91). opinions of the experts (96). Techirghiol sapropelic mud is one of the natural Yet, in the literature, mineralogical and chemical therapeutic factors of medical use in Romania, being compositions and the possible toxicity of the peloids (97) represented by the deposit on the bottom of lake need to be investigated and compared with some limits to Techirghiol; it has been and still is a subject to ongoing determine whether they have any health benefits and medical research because of the need of its medical use potential applications for pelotherapeutic treatments (26). for scientific evidence-based medicine (92). One of the On the other hand, the therapeutic Euganean thermal mud interesting papers regarding Techirghiol mud’s post- is a unique product of the Euganean Thermal District resorptive effects, refer to the plasmatic level variations (Italy) that represents the largest and oldest thermal of leptin show a different response depending on the center in Europe (54). The application of the therapeutic balneal application type. Warm mud application leads to mud, whose beneficial effects have been documented a significant decrease of the leptin level which translates since Ancient Roman times, is recognized by the Italian into the remission of inflammation and rheumatic pain. Health System as a healing treatment for arthro- Cold mud application as a contrasting therapy leads to an rheumatic diseases. The beneficial mud is obtained by a increase of the leptin values at the end of the treatment, specific maturation procedure that can be considered as an increase that is not statistically significant. The lack of an ancient biotechnological process. This process is now leptin variation in the case of the group that underwent coded by a protocol to be followed to obtain the “Mature constant therapy is due to the thermoregulation function Mud AOC” certification. The mud maturation process that is highly strained during the cold application, while begins when virgin clay, obtained from the lakes of the thermal comfort during baths neutral from a thermal Arquà Petrarca (Padova, Italy), is laid in open-air tanks or point of view stabilizes the hypothalamus function and silos of the different thermal Spas, and maintained there does not request major neuroendocrine answers. Recent for a period of at least two months, constantly covered by data indicate that the hypothalamus is targeted by leptin a layer of flowing thermal water, at the indicated actions, leptin which crosses the hematoencephalic temperature of 38–40 ◦C. This maturation procedure barrier and interacts with the leptin receptor in the arcuate allows a microbial community, mainly represented by nucleus of the hypothalamus, thereby controlling the cyanobacteria, to grow on the mud surface. thyroid-stimulating hormone, the melanocyte-stimulating Microorganisms, embedded in a thick polysaccharidic hormone, and gamma-aminobutyric acid, which will matrix, generate a green biofilm that indicates the correct eventually modulate the metabolic answers of the body mud maturation. Before using the mud for therapies, this (93). is mixed and put in tanks in which thermal water at 5. DISCUSSION nearly 60 ◦C is present, to reduce the natural microbial The use of mud by humans for medicinal and wellness load and maintain the fluidity of the product (98). purposes is most probably as old as mankind. Additionally, Techirghiol represents ancient golf of the Balneotherapy is an effective complementary approach in Black Sea, with sapropelic mud extracted from the lake, the management of several low-grade inflammations and associated with marine climatic characteristics in a stress-related pathologies, especially rheumatic and combined heliomarin and thalassotherapy cures. In BRST metabolic conditions. However, despite the demonstrated are treated patients with a wide range of diseases, most of clinical and symptomatic benefits of these therapies, their them with osteoarticular and neurological pathology, both role in modern medicine is still controversial, mainly adults and children. Yearly, in Balneal and Rehabilitation because the biological mechanisms underlying these Sanatorium from Techirghiol, are admitted more than ten benefits have not yet been completely elucidated. In the thousand patients. The patients are admitted for a period context of these pathologies, further studies are necessary of 12 days up to 30 days and they receive complex to clarify the mechanisms of effects involving the stress rehabilitation treatment: hydro-kinetic-therapy in the response and, consequently, its interaction with the salted water of the pool, alternated with warm mud baths inflammatory response (42). or hot mud wrapping, or cold mud ointment, and then

swim in the lake, completed with massage, Kinesiotherapy (therapeutic exercises including electrotherapy, and kinesiotherapy. All patients stretching, isotonic, isometric, and isokinetic underwent an initial clinical examination and then the strengthening), is effective in improving pain, joint physician filled up a questionnaire, which includes stiffness, functional mobility and muscle strength in personal data, information about the disease requiring patients with knee OA. There are new data that admission if the patient has in the medical history any emphasize the efficiency of the combined effect of balneal treatment and what were the results, and finally geotherapy with kinesiotherapy in reducing pain for the group of affections to which fit the existing symptoms patients with osteoarthritis (102). (99). 6. Conclusions Delivery of drugs on/into/through the skin enables either This paper overviews the current state-of-the-art local or systemic actions and improvement of poor knowledge in the approach of peloidotherapy in biopharmaceutics profiles of drugs administered via other rehabilitation, with a focal point on the therapeutic administration paths, and becomes a useful strategy in properties of peloids. Most of the thermal spas around the situations in which other administration routes are not world recommend their mud baths or local mud possible or inadvisable. Pelotherapy is the topical cataplasm applications, as they recognize therapeutic administration of hot-muds or peloids, with optimal results through their anti-inflammatory, analgesic, and rheological and thermal properties composed of clay antiseptic effects on musculoskeletal and dermatologic minerals and mineral-medicinal water aimed at treating pathologies, which are increasingly supported by clinical arthro-rheumatic issues, bone-muscle traumatic damage, trials (103). Guidelines and studies reviewed are and dermatological pathologies. Most of the important recognizing the beneficial effects and mechanisms of properties attributed to clays for dermo-cosmetic action of mud therapy (12). Osteoarthrosis is the most applications are related to their surface properties addressed pathology (104)(105). (surface area, cation exchange capacity, layer charge, The works we have evaluated show that almost half of among others); rheological properties (thixotropy, the thereof included patients originate from Romania. rheopecty, viscosity, plasticity); and other physical and Our systematic review and meta-analysis have mechanical properties including particle size and shape, emphasized an additional, corollary, conclusion, too: the color, softness, opacity, reflectance, iridescence, and so often connected/ synergistic, therapeutic, and on (21). rehabilitative effects of the balneary interventions (46), The paucity of evidence about cost-effectiveness and including mud procedures based, prove and strengthen economic evaluation of conservative, non- the Romanian successfully paradigm of a unitary/ sole pharmacological and non-surgical rehabilitative specialty: Physical and Rehabilitation Medicine & interventions for the range of lower limb musculoskeletal Balneology – and this is reflected also in the new focus complaints is a concern for one found study (100). and title of our publication ”Balneo and PRM Research Balneotherapy could be beneficial in treating patients Journal”. suffering from low back pain, but there is still not enough 7. Funding quality scientific evidence (101). This research did not receive any specific grant from Mud produces important beneficial effects including anti- funding public, commercial, or not-for-profit agencies. inflammatory and anti-microbial activity which might 8. Acknowledgments explain in part the therapeutic properties of mud packs This study, being a systematic review, did not require against chronic inflammatory skin disorders. Besides, written consent from the patients involved. treatment of keratinocytes with mud extract led to a All authors have equally contributed to this article. significant increase of ATP levels as well as mRNA 9. Declaration of interests expression of genes involved in cell protection and Authors declare no competing interests. The approval of longevity. The mud could serve as a natural anti-oxidant the Ethics Commission of „Bagdasar-Arseni Hospital” in and moisturizing anti-aging agent with important Bucharest (N.O. 9910/17.03.2021) was obtained for this cosmeceutical applications (34). article.

Figures and tables TABLE 1 Step I: numerical search results. Articles Keywords Web of Science Cochrane Elsevier PubMed PMC PEDro Total Articles found in "Mud therapy" 44 1 7 69 41 15 177 the first phase "Peloidotherapy" 13 4 2 7 5 0 31 "Pelotherapy" 52 2 2 14 29 0 99 "Fango therapy" 0 1 0 0 0 0 1 "Mud therapy" + "rehabilitation" 11 1 5 20 21 0 58 "Peloidotherapy" + "rehabilitation" 2 0 1 3 2 0 8 "Pelotherapy" + "rehabilitation" 3 0 0 4 13 0 20 "Fango therapy" + "rehabilitation" 0 0 0 0 0 0 0 TOTAL 125 9 17 117 111 15 394 9

Figure 1: Flow-chart depicting the literature search and selection strategy. After applying the inclusion and exclusion criteria

TABLE 2 OpenMeta-Analyst source files related to pathologies/country patients treated by mud therapy

s m

ain

l P

nia oid arthritis oid rde oskeletal oskeletal ack oporosis

Year taly OA e I B Spain oma France Turkey Contro Hunga R diso total patients

Ost ow - lgic sympt lgic L A Muscul N THER COUNTRY Rheumat O Study AXIS LEGEND 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Karagülle (3) 2015 404 0 0 0 0 404 0 202 0 0 0 0 360 0 44 Morer (5) 2016 1118 599 308 64 0 147 0 535 0 0 397 156 0 0 721 Fioravanti (55) 2015 95 95 0 0 0 0 0 46 0 0 0 0 0 95 0 Fioravanti (106) 2015 103 53 0 0 0 0 0 50 0 0 0 0 0 103 0 Yücesoy (57) 2018 139 0 0 0 0 139 0 139 0 0 0 139 0 0 0 Forestier (58) 2016 2233 1721 0 0 0 0 0 512 0 132 117 330 642 378 634 Özkuk (32) 2017 50 50 0 0 0 0 0 50 0 0 0 50 0 0 0 Pascarelli (107) 2016 103 53 0 0 0 0 0 50 0 0 0 0 0 103 0 Eröksüz (70) 2019 50 0 0 0 0 0 50 50 0 0 0 50 0 0 0 Gungen (44) 2016 59 34 0 0 0 0 0 25 0 0 0 59 0 0 0 Valckenaere (108) 2018 185 0 0 0 92 0 0 93 0 0 0 0 185 0 0 Gyarmati (83) 2017 47 47 0 0 0 0 0 24 0 0 47 0 0 0 0 Tenti (31) 2020 212 212 0 0 0 0 0 212 0 0 0 0 0 212 0 Cantista (7) 2020 120 60 0 0 0 0 0 60 0 0 0 0 0 0 120 Alfier (102) 2020 48 48 24 0 0 0 0 24 0 0 0 0 0 0 48 Hahm (53) 2020 32 0 0 0 0 16 0 16 0 0 0 0 0 0 32 Aksoy (47) 2017 63 33 0 0 0 0 0 30 0 0 0 63 0 0 0 Kim (87) 2020 41 22 0 0 0 0 0 19 0 0 0 0 0 0 41 Ionescu (85) 2017 46 23 0 0 0 0 0 23 46 0 0 0 0 0 0 López (101) 2019 1390 0 0 0 0 1390 0 0 0 0 71 81 1192 0 46 Xiang (60) 2016 1010 1010 0 0 0 0 0 0 0 132 53 236 451 80 58 Gálvez (62) 2018 36 36 0 0 0 0 0 36 0 36 0 0 0 0 0 Iliescu (99) 2018 6281 2744 0 0 0 2273 0 0 6281 0 0 0 0 0 0 Varzaityte (65) 2019 92 32 0 0 0 0 0 60 0 0 0 0 0 0 92 Király (66) 2019 60 60 0 0 0 0 0 60 0 0 60 0 0 0 0 Hou (104) 2020 1106 440 0 0 0 0 0 411 0 121 53 151 451 290 50 TOTAL 15123 7372 332 64 92 4369 50 2727 6327 421 798 1315 3281 1261 1886 % 100 48.75 2.20 0.42 0.61 28.89 0.33 18.03 41.84 2.78 5.28 8.70 21.70 8.34 12.47 10

Figure 2: Pathologies and Country frequencies in mud therapy studies (see LEGEND in Table 3)

Binary Random-Effects Model Metric: Proportion Model Results Estimate Lower bound Upper bound Std. error p-Value 0.544 0.400 0.687 0.073 < 0.001 tau^2 Q(df=25) Het. p-Value I^2 Heterogeneity 0.138 1447636.745 < 0.001 99.995

Figure 3: Studies Heterogeneity - forest-plot (80)

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